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Blood, 9 July 2009, Vol. 114, No. 2, pp. 459-468. Prepublished online as a Blood First Edition Paper on May 4, 2009; DOI 10.1182/blood-2008-12-195859.
TRANSPLANTATION In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta1 ITB-CNR, Milan, Italy; 2 Istituto Clinico Humanitas, Rozzano, Italy; 3 Department of Biochemistry, University of Pavia, Italy; 4 Orthopedic Research Laboratories, University of Michigan, Ann Arbors; 5 Section on Physical Biochemistry, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD; 6 Laboratorio di Tecnologia Medica, Istituti Ortopedici Rizzoli, Bologna, Italy; 7 Bone Metabolic Unit San Raffaele Scientific Institute, Milan, Italy; 8 Department of Experimental Medicine, Section of Histology and Embryology, University of Pavia, Pavia, Italy; and 9 Section on Connective Tissue Disorders, Bone and Extracellular Matrix Branch (BEMB), NICHD, NIH, Bethesda, MD
Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases. 
